REVIEW

A Review of the Efficacy of Thalidomideand Lenalidomide in the Treatment of RefractoryPrurigo Nodularis

Victoria M. Lim . Eric L. Maranda . Vivek Patel . Brian J. Simmons .

Joaquin J. Jimenez

Received: April 29, 2016 / Published online: June 11, 2016� The Author(s) 2016. This article is published with open access at Springerlink.com

ABSTRACT

Prurigo nodularis (PN) is a chronic dermatoses

characterized by intensely pruritic, excoriated,

or lichenified nodules. Standard therapy

includes corticosteroids, antihistamines, and

phototherapy; however, treatment results are

often inadequate or transient. Thalidomide

and its analogue lenalidomide are

immunomodulatory drugs that have

successfully been used to treat refractory cases

of PN. A systematic review was performed

evaluating the use of thalidomide and

lenalidomide for PN. Eighteen articles were

included in this study in which a total of 106

patients were evaluated, of whom 76 (71.7%)

had moderate to significant improvement of PN

with the use of thalidomide, lenalidomide, or

both. Patients given thalidomide were treated

with doses of 50–300 mg daily for

1–142 months, with the majority being treated

for less than 1 year. Patients treated with

lenalidomide were given a daily dose of

5–10 mg from 3 to 24 months. The most

common side effects observed were sedation,

gastrointestinal symptoms, and transient

peripheral neuropathy. While thalidomide and

lenalidomide are drugs that have shown

promising results in these studies, caution

should be taken in prescribing these

medications and patients should be informed

about the potential side effects. As such,

large-scale randomized controlled trials with

long-term follow-up are needed to determine

appropriate dosing, efficacy, and toxicity

profiles.

Keywords: Nodular prurigo; Lenalidomide;

Prurigo nodularis; Pruritus; Thalidomide;

Treatment

Enhanced content To view enhanced content for thisarticle go to http://www.medengine.com/Redeem/F6D4F0602F038A59.

Victoria M. Lim and Eric L. Maranda are co-first authorsand equally contributed.

V. M. LimCreighton University School of Medicine, Omaha,NE 68102, USA

E. L. Maranda (&) � V. Patel � B. J. Simmons �J. J. JimenezDepartment of Dermatology and CutaneousSurgery, University of Miami Miller School ofMedicine, 1475 NW 12th Ave., Suite 2175,Miami, FL 33136, USAe-mail: emaranda@med.miami.edu

Dermatol Ther (Heidelb) (2016) 6:397–411

DOI 10.1007/s13555-016-0122-9

INTRODUCTION

Prurigo nodularis (PN) of Hyde, also known as

nodular prurigo, is a chronic skin disease of

unknown etiology. It is characterized by an

intensely pruritic papulonodular eruptions. The

hyperkeratotic lesions tend to be symmetrical

and occur over the extensor surfaces of the

extremities. PN has been associated with a range

of systemic conditions such as HIV/AIDS,

depression, gastrointestinal disorders,

hypothyroidism, and hematologic

malignancies. In most cases, however, the

etiology is unclear [1–4]. First-line therapy for

PN is comprised of topical antipruritics or

corticosteroids, oral steroids, antihistamines,

or certain antidepressants such as doxepin [5].

Additional commonly used treatments include

phototherapy, capsaicin, cyclosporine, and

methotrexate [3]. Recently, novel agents such

as tumor necrosis factor (TNF) inhibitors

alfacept and etanercept have also been

prescribed [14]. Most of these therapies,

however, are ineffective or only provide

temporary relief. Thus, alternative treatments

are needed for refractory cases.

In 1965, Sheskin was the first to report on

the use of thalidomide to treat a patient with PN

[6]. Thalidomide is a drug with numerous

proposed mechanisms of action and effects,

ranging from acting as a prostaglandin/

histamine antagonist to being an inhibitor

of fibroblast growth factor and a

immunomodulatory agent [7]. As an

immunomodulatory drug, thalidomide

functions to decrease TNF-a and inhibits

polymorphonuclear leukocyte chemotaxis [7].

TNF-a induces pain by increasing the

production of interleukin (IL)-1b and IL-6,

which then increases the production of IL-8, a

known mediator of sympathetic pain [8–10].

More recently, thalidomide has also been

shown to inhibit the peripheral vanilloid

receptor 1 (TRVP1) channel, which is also

involved in pain sensation [11].

Thalidomide became well known for its

teratogenic effects leading to severe fetal

malformations when taken by pregnant

women before the third trimester [12]. This

medication has other known side effects, which

include peripheral neuropathy, somnolence,

altered mood, thrombosis, and gastrointestinal

symptoms.

Lenalidomide, a more potent analogue of

thalidomide, has been most commonly used to

treat multiple myeloma and myelodysplastic

syndromes. Lenalidomide’s molecular structure

varies by one less carbonyl group but one

additional amine compared to thalidomide

[13]. This change confers a different toxicity

profile and, as such, lenalidomide has a much

lower frequency of peripheral neuropathy [14].

While some studies report the use of

thalidomide and lenalidomide to be beneficial

for the treatment of PN, their use in the

management of PN remains controversial.

Thus, this review aims to explore and review

the efficacy and safety of thalidomide and

lenalidomide for the treatment of refractory PN.

METHODS

A systematic literature review was performed to

identify articles between January 1, 1970 and

February 15, 2016 relevant to the treatment of

prurigo nodularis with thalidomide or

lenalidomide. The terms ‘‘prurigo nodularis OR

nodular prurigo OR picker’s nodules OR lichen

corneus obtusus OR atypical nodular form of

neurodermatitis circumscripta’’ were searched

in the National Library of Medicine’s PubMed

Database and returned 350 articles. Exclusion

criteria included articles that were not written

in English and those that were not original

398 Dermatol Ther (Heidelb) (2016) 6:397–411

clinical trials, case series or case reports. Thirty

manuscripts with relevant titles and abstracts

were included for further review, based on case

reports/series due to lack of controlled studies.

If a study with a cohort or group did not

distinguish patients with PN from other

patients with different dermatological

conditions within the same group, it was

excluded. In addition, the SCOPUS Database

was crosschecked, but no additional articles

were found. As a result, a total of 18 articles

were selected for inclusion in this review

(Fig. 1). This article is based on previously

conducted studies and does not involve any

new studies of human or animal subjects

performed by any of the authors.

RESULTS

In the first reported case, Van de Broek et al.

described a 57-year-old man with refractory PN

admitted for an infection superimposed on

nodules that had previously failed both topical

and oral steroids as well as antihistamines [12].

Thalidomide 100 mg bis in die (BID) was used

for 3 months and discontinued after resolution

of the pruritis and lesions. No side effects were

reported.

Andersen and Fogh retrospectively reviewed

42 subjects with PN treated with thalidomide

[22]. Of these, 60% of patients showed clinical

improvement, but 9.5% of patients showed no

effect. The average daily dose was 100 mg,

though a few patients received 50 mg due to

gastrointestinal-related side effects. The mean

duration of treatment was 105 weeks, and

59.5% of patients developed peripheral

neuropathy ranging from 1 week to 7.5 years

after initiation of treatment, prompting

discontinuation of therapy at the time of

symptom development. None of the subjects

with neuropathy showed evidence of this

adverse effect during follow-up.

Alfadley et al. started thalidomide 100 mg

BID in a Hepatitis B patient who developed

major depressive disorder and suicidal risk

Fig. 1 Flowchart of search methodology. PN prurigo nodularis

Dermatol Ther (Heidelb) (2016) 6:397–411 399

following a 5-year history of PN refractory to

therapy [17]. After 3 weeks of treatment, the

pruritus had mildly decreased without

improvement in skin lesions. Subsequently,

the dose was increased to 300 mg daily. By the

8th month, the pruritus had ceased, the

majority of lesions had cleared, and mild

sensory loss developed. The patient was then

placed on a maintenance dose of 50 mg every

other day for 3 months. At the 4-month

follow-up, the patient remained disease-free

and the sensory loss had dramatically

improved.

Maurer et al. performed a trial on 10

HIV-infected patients. They received

thalidomide 100 mg per day and were

randomized after 1 month to receive either

100 or 200 mg daily [4]. Doses were adjusted if

adverse events appeared, thus daily dosing

ranged from 33 to 200 mg. Eight patients

(80%) continued the trial longer than

1 month, and all had a greater than 50%

reduction in itch, while 7 (70%) had a greater

than 50% reduction in lesions. Pruritic

reduction occurred within 1–3 months of

treatment, while decreases in erythema and

nodule size occurred between 3–6 months.

Three patients (30%) developed peripheral

neuropathy; however, no association with

neuropathy was found between treatment

duration, daily dose, or cumulative dose.

Herranz et al. also treated a case of

AIDS-associated PN in a 35-year-old white

male with a CD4 count of 8 cells/mm3 [2].

Following a failed trial of topical corticosteroids

and antihistamines, he was placed on

thalidomide 100 mg daily for 6 weeks, upon

which there was a drastic improvement of

itching and lesions. The patient had a relapse

of tuberculosis after 1 month of discontinuing

thalidomide, which was postulated to have

been due to the inhibitory effect of

thalidomide on TNF-a. There were no other

side effects reported.

Ferrandiz et al. conducted a prospective trial

to evaluate combination therapy using

thalidomide and ultraviolet-B (UVB)

irradiation on four patients with PN [15]. Two

patients had previously undergone a course of

thalidomide but subsequently relapsed.

Thalidomide was started at 100 mg daily and

was discontinued once significant clinical

improvement was achieved, ranging from 8 to

16 weeks. UVB phototherapy was then initiated

for three sessions per week until complete

clearance of the nodules was achieved, with a

maximum of 70 exposures allowed. Most

symptoms resolved after 6–12 UVB treatments,

at which point thalidomide was also

discontinued. One patient developed

temporary peripheral neuropathy and another

developed nausea. The follow-up period ranged

from 4–18 months, in which one patient

experienced a relapse at 5 months, which was

then successfully managed with 35 treatments

of UVB irradiation.

Lenalidomide has also been used in patients

experiencing toxicity with thalidomide. Kanavy

et al. treated a 45-year-old black woman with a

severe 10-year case of PN [14]. She was first

treated with thalidomide 200 mg daily and had

a dramatic improvement, but she developed

neuropathy after 18 months and treatment was

stopped. After thalidomide, she also was treated

with oral naltrexone, minocycline, gabapentin,

alafecept, and etanercept with no sucess [14].

Thereafter, she was started on lenalidomide

5 mg a day and by the second week she noted

a significant decrease in pruritus, sleep, and

concentration ability. By the first month, she

exhibited healing of nodules and disappearance

of itching. Two attempts were made to taper her

dose and both resulted in disease flare-ups, thus

she was maintained on 5 mg/day for a total of

400 Dermatol Ther (Heidelb) (2016) 6:397–411

24 months. The patient remained in remission

after 2 years. Liu et al. reported another case of

lenalidomide-treated refractory PN. The patient

had a severe 20-year history of the disease. She

was previously treated with steroids,

antihistamines, and underwent

psoralen ? UVA therapy for 6 months with no

relief. Furthermore, the latter treatment resulted

in the development of squamous cell

carcinomas on her lower extremities. After

discontinuation of the photochemotherapy,

she was started on 100 mg of thalidomide

daily. By month 3, she developed tingling and

numbness in all of her limb extremities and

thalidomide was discontinued. After 1 month,

she resumed thalidomide at 50 mg but her

neuropathy returned and the medication was

discontinued. Four months later, she was

started orally on lenalidomide 10 mg/day with

a marked reduction in nodules and itching

intensity after only 1 month. Her reported

adverse effects were arthralgias, nausea, and

vomiting. She continued taking lenalidomide

and achieved almost complete clearance until

right leg weakness prompted termination of the

current treatment after 3 months of

lenalidomide. She had no residual neuropathy,

but her PN relapsed.

TRENDS IN TREATMENT, DOSAGE,AND LENGTH

A total of 18 studies with 106 patients treated

with thalidomide or lenalidomide for PN were

reviewed (see Tables 1, 2). It should be noted

that these trends were based on case reports/

series or retrospective literature due to lack of

controlled studies, especially in regards to

lenalidomide treatment, as only a few case

reports exist. In the earlier studies, patients

were started on higher doses of thalidomide of

200 mg or more daily [5, 12]. In the majority of

studies since then, however, patients were

started on an initial dose ranging from 50 to

200 mg thalidomide per day and then tailored

according to response or development of side

effects. Length of treatment for thalidomide

ranged from 1 month to almost 12 years

depending on remission of disease or

discontinuation due to development of

toxicity. In the study by Ferrandiz et al.,

patients were treated with combination

therapy of thrice weekly narrow-band UVB

phototherapy and thalidomide at 100 mg daily

for 2.5–5 months [15]. Excellent responses were

achieved after an average of 3 months on

thalidomide and 32 UVB courses [15]. One

patient that was taking lenalidomide was kept

on 5 mg for over 2 years, while the other took

10 mg daily for 3 months [11, 13]. For

lenalidomide, treatment length was from 3 to

over 24 months. Lenalidomide offered a

relatively low toxicity treatment to patients

who had toxicity to thalidomide.

TRENDS IN OUTCOMES

A total of 106 patients were included in this

review, 76 (71.7%) of whom showed significant

improvement in reduction of pruritus and

disappearance of nodules [1, 2, 4, 14–28].

Only slight or mild improvement was seen in

11 (10.3%) patients [23, 25, 26], while 15

(13.3%) patients showed no improvement at

all [19, 23, 25, 26, 29]. Results were unable to

be determined in four patients in one

retrospective study [25]. Pruritus typically was

the first to decrease with a noticeable clinical

difference by 2–4 weeks followed by flattening

of lesions and decreased excoriation which

occurred at an average of 2 months. For

patients who achieved complete or almost

Dermatol Ther (Heidelb) (2016) 6:397–411 401

Table1

Studiesutilizing

thalidom

idefortreatm

entof

prurigonodularis

Stud

yPatients

M:F

Age

(years)

Doseperday(m

g)Duration

(mon

ths)

Results

Adverse

effects

Follo

w-up

(mon

ths)

Van

deBroek

[16]

11:0

54200mg

3Lesions

gradually

flattened

andpruritus

disappeared

None

–

Clemmensen

etal.[29]

31:2

29–6

9200mg

200mgwith

maintenance

dose

of

50mg

300mg

6–22

Twopatientsreported

pruritus

resolved

and

alllesionshealed.O

ne

patientshow

edno

improvem

entin

symptom

s

Twodeveloped

paresthesias

inhand

s

after11–1

8months,

onehadadverseeffects

persist[

1year

after

discontinu

ation.

Two

hadasym

ptom

atic

carpaltunn

el

synd

rome

12

Winkelmann

etal.[17]

40:2(two

unknow

n)

55,5

9,(two

unknow

n)

300mgthen

taperedto

100mg

100mgthen

increased

to200mg.After

relapse,second

course

was

maintainedat

200mg

3–9

Allshow

edmarked

reductionin

pruritus

by1month

and

flatteningof

lesionsby

2months.Two

remainedin

remission

at2and3years

follow-up,

two

relapsed

within

2weeks

andrequired

a

second

course

Nosignificant

adverse

effects.Side

effects

reported

included

indigestion,

constipation,

nervousness,and

sedation

24–4

8

Bergeret

al.

[1]

11:0

49200mgthen

ranged

from

100to

150mg

for9months

14At2months,adram

atic

decrease

innu

mberof

active

lesions

At5months,the

pruritus

disappeared

Mild

peripheral

neuropathy

oflegs

that

may

bedueto

either

PNor

HIV

medications

2.75

402 Dermatol Ther (Heidelb) (2016) 6:397–411

Table1

continued

Stud

yPatients

M:F

Age

(years)

Doseperday(m

g)Duration

(mon

ths)

Results

Adverse

effects

Follo

w-up

(mon

ths)

Herranz

etal.

[2]

11:0

35100mg

1.5

Dramaticim

provem

ent

ofcutaneouslesions

anddisappearanceof

thepruritus

Nonereported

1

Crouchet

al.

[19]

51:4

23–7

1100mg

1–3.5

Three

show

ed

improvem

entof

lesions,twohadno

change

Three

patientsceased

treatm

entdueto

adverseevents,two

from

peripheral

neurotoxicityandone

from

dizziness,angina,

andworsening

diabetes

4

Alfadley

etal.

[20]

11:0

37100mgb.i.d,for

3weeks

increasedto

300mgq

daily

for8months,

then

taperedto

maintenance

of50

mg

q48

hfor3months

19After

8months,mostof

thelesionsand

pruritus

resolved

At8months,developed

mild

sensoryloss,then

developedtotal

peripheralneuropathy

which

prom

pted

discontinu

ation.

At

4-month

follow-up

thesymptom

s

improved

4

Dermatol Ther (Heidelb) (2016) 6:397–411 403

Table1

continued

Stud

yPatients

M:F

Age

(years)

Doseperday(m

g)Duration

(mon

ths)

Results

Adverse

effects

Follo

w-up

(mon

ths)

Maureret

al.

[4]

8–

–100mgthen

rand

omized

to100or

200mg(range

from

33to

200mg)

1–23

(avg.

8)

Eight

had[50%

response

inreduction

ofpruritus

over

3.4months(average).

Sevenhad[50%

reductionof

skin

involvem

entover

5months(average).

Four

patientswere

followed

upfor

1.5–

9.5monthsafter

treatm

entandthree

maintaineda[50%

response

andthelast

relapsed

Three

developed

thalidom

ide

peripheralneuropathy

(one

at1month,two

at7months).A

ll

threeim

proved

2–3monthsafter

cessation.

Weight

gain,constipation,

sedation,cognitive,

andmoodchanges

werealso

noted

1.5–

9.5

Sharmaet

al.

[21]

11:0

44100mgfor2weeks

increasedto

200mg

for2months

2.5

Com

pleteresolution

of

lesions

Sedation

–

Lan

etal.[22]

64:2

40–8

6100mgthen

tapered

1.5–

15Allreported

prom

inent

reductionin

pruritus

andreduced

excoriationof

skin

lesions.One

had

recurrence

andwas

treatedwithasecond

course,w

hich

proved

successful

Twohadsedation,o

ne

hadgeneralized

erythemawithlower

legedem

athat

resolved

without

intervention

after

3weeks

0–20

404 Dermatol Ther (Heidelb) (2016) 6:397–411

Table1

continued

Stud

yPatients

M:F

Age

(years)

Doseperday(m

g)Duration

(mon

ths)

Results

Adverse

effects

Follo

w-up

(mon

ths)

Doherty

and

Hsu

[23]

12–

–100mgtaperedto

50mgifearlyclinical

improvem

ent

Over1

One

hadmild

(no

worsening

and\25%)

improvem

ent,sixhad

moderate(25–

90%)

improvem

ent,andone

hadcomplete([

90%)

improvem

ent

Num

bness,constipation,

andsedation

–

Orlando

etal.

[24]

10:1

52100mgfor1month,

50mgfor2months,

then

dosage

increased

to100mgfor

1month,and

reduced

againto

maintenance

of50

or100mgorally

alternatedays

6After

1month,p

ruritus

decreasedandskin

exam

inationrevealed

that

mostlesionshad

disappearedor

flattened.A

fter

4month,sdose

was

increasedback

to

100mgandleg

nodulesshow

ed

significant

decrease

in

size

andnu

mber

Nosignificant

side

effectsreported

6

And

ersenetal.

[25]

4217:25

Avg.4

6Avg.1

00mgdaily

Four

patientsdecreased

to50

mgdueto

gastrointestinalside

effects

Avg.26.25

25patientshad

significant

improvem

ent,sixhad

mild

improvem

ent,

andonehadcomplete

clearing.S

ixhadno

affect

andfour

were

lostto

follow-up

25reported

transient

peripheralneuropathy

(at89

weeks

average),

nine

hadsedation,

sevenhaddizziness,

andfivedescribeda

rash

–

Dermatol Ther (Heidelb) (2016) 6:397–411 405

Table1

continued

Stud

yPatients

M:F

Age

(years)

Doseperday(m

g)Duration

(mon

ths)

Results

Adverse

effects

Follo

w-up

(mon

ths)

Taefehn

orooz

etal.[26]

133:10

37–6

8(avg.

49.7)

50–1

00mgfor12

patients

150–

200mgfor1

patient

3–142

Sevenshow

edcomplete

improvem

entafter

3months(average)

withfour

on

maintenance

treatm

entat

last

follow-up.

Four

show

edslight

improvem

entand

treatm

entfortwowas

judged

tobe

unsuccessful

Four

patients

discontinu

ed

treatm

entdueto

peripheral

neuropathy),renal

toxicity,o

rsedation

anddizziness.One

patientlostto

follow-up

6–119

Rishi

etal.

[28]

10:1

4550

mgdaily

initialthen

increasedto

100mg

andthen

150mg

–Significant

reductionin

pruritus

that

allowed

fordiscontinu

ationof

corticosteroids

Experienced

peripheral

neuropathy

athigher

dosesrequiring

reductionto

50mg

daily

–

Avg

average,hx

history,ptspatients,y/o

yearsold,

b.i.d.b

isin

die

406 Dermatol Ther (Heidelb) (2016) 6:397–411

Table2

Studiesutilizing

thalidom

idewithUVBor

lenalidom

idefortreatm

entof

prurigonodularis

Stud

yPatients

M:F

Age

(years)

Treatment

Doseperday

(mg)

Duration

(mon

ths)

Results

Adverse

effects

Follo

w-up

(mon

ths)

Ferrandiz

etal.

[15]

4–

53–7

4Thalidom

ide?

UVB

100mg

2.5–

5months

After

anavg.of

3months

onthalidom

ide,

pruritus

was

greatly

reducedandlesions

flattened.T

hen,afteran

avg.of

8UVBsessions,

mostlesionshad

disappeared.

Com

plete

remission

was

achieved

afteran

avg.of

32UVB

treatm

ents

One

patienthad

reversible

peripheral

neuropathy

and

onehadnausea

4–18

Kanavy

etal.

[14]

10:1

45Lenalidom

ide

5mgfor

4months,

decreasedto

everyotherday,

then

every4th

day,then

increasedback

to5mgdueto

flare

ups

Over

24months

Within2weeks,n

oticed

significant

reductionin

pruritus

and

improvem

entin

sleep,

mood,

andability

to

concentrate.After

1month,h

adnear

completeresolution

of

pruritus

andvisible

healingof

theprurigo

nodules.Whendose

waslowered,the

patient

developedworsening

pruritus

Initially

somnolence

andfatigue,but

thisresolved

after

changing

to

bedtim

edosing

24

Dermatol Ther (Heidelb) (2016) 6:397–411 407

complete remission, time until that endpoint

varied from as little as 1 month to as long as

8 months [20].

TRENDS IN ADVERSE EFFECTS

Peripheral neuropathy was the most common

adverse effect. Overall, there were a reported 39

(36.8%) cases of peripheral neuropathy

[1, 4, 15, 16, 18–20, 25–28] not including the

additional patients affected in Doherty and

Hsu’s study, as the exact amount was unable

to be obtained [23]. Thalidomide-induced

neuropathy developed after 1 week to 7.5 years

of treatment [25]. In most cases, the peripheral

neuropathy was reversible and took up several

months to resolve. Some patients with HIV/

AIDS experienced peripheral neuropathy, but it

was unclear if it was due to thalidomide or the

HIV infection [1]. Clemmensen et al. had one

patient who still experienced neuropathy over a

year after discontinuation; however, it should

be noted that the patient used the drug for

18 months [29]. Although no studies directly or

extensively addressed the subject, there appears

to be increased toxicity at higher doses of

thalidomide [14, 20, 22, 26]. Sedation,

gastrointestinal symptoms, and dizziness were

the other most-often reported adverse effects.

Lenalidomide was used in two patients after

they failed thalidomide therapy [14, 27]. The

first patient discontinued thalidomide after

developing peripheral neuropathy. She was

then treated successfully with lenalidomide

and had no recurrence of paresthesias [14].

The other patient also developed tingling and

decreased sensation with thalidomide; however,

she eventually re-developed neuropathy after a

trial of lenalidomide [27]. More studies are

needed to determine the outcomes of

thalidomide compared to lenalidomide, and

Table2

continued

Stud

yPatients

M:F

Age

(years)

Treatment

Doseperday

(mg)

Duration

(mon

ths)

Results

Adverse

effects

Follo

w-up

(mon

ths)

Liu

etal.

[27]

10:1

64Lenalidom

ide

10mg

3months

After

1month,h

ad

significant

reductionin

numberof

nodulesand

pruritus,continu

edto

improveover

thenext

2months,butrelapsed

afterdiscontinu

ation

Mild

side

effects

(nausea,vomiting,

malaise,

arthralgia),and

after3months,

weaknessin

right

legprom

pted

discontinu

ation

–

408 Dermatol Ther (Heidelb) (2016) 6:397–411

whether this could be a preferred treatment

option with less side effects.

TRENDS IN RECURRENCE

Seven patients relapsed after

thalidomide-induced improvement of PN

symptoms and cessation of therapy

[14, 15, 17, 22, 27]. Four achieved remission

after a second course of completed therapy

[15, 17, 22], and one continued to have disease

flare-ups with multiple attempts at tapering the

dose, and thus was maintained on 5 mg/day of

lenalidomide [14]. The last one had to stop

treatment after courses of both thalidomide and

lenalidomide due to neuropathy, and relapsed

without further resolution [27].

CONCLUSION

Prurigo nodularis is a severely pruritic skin

disease and standard therapy often yields

unsatisfactory results. Thalidomide and

lenalidomide can be effective alternative

treatments for refractory PN, though optimal

dosage and treatment time varied in the

reviewed studies. Clinical data compiled in

this review show that individuals with severe

disease experienced the most significant

reduction in pruritus and improvement in the

appearance of skin. Historically, thalidomide

has been used with reluctance due to toxicity;

however, the incidence and persistence of

adverse effects including neuropathy is highly

variable among patients, in the majority of

whom clinical improvement preceded the

development of permanent deficit. Ideal

treatment length and dosing regimens may

help abate most side effects. To further avoid

adverse effects, thalidomide could be used in

sequential combination therapy with UVB or

followed by its analogue lenalidomide. Both

options shorten the treatment length for

thalidomide and may limit adverse reactions;

however, most studies are limited by virtue of

being case reports and their low power. In the

contemporary era of targeted therapy, an

enhanced understanding of the biology and

related physiology of PN will allow clinicians to

more optimally treat this evasive disease.

Additionally, understanding of the molecular

mechanisms of thalidomide and lenalidomide

may also further elucidate their role in the

treatment of PN. Given the findings in the

aforementioned studies, thalidomide and its

analogues should be further evaluated in a

prospective manner with the aim of improving

efficacy and reducing treatment-related toxicity

by determining the most effective dosing and

treatment time.

ACKNOWLEDGMENTS

No funding or sponsorship was received for this

study or publication of this article. All named

authors meet the International Committee of

Medical Journal Editors (ICMJE) criteria for

authorship for this manuscript, take

responsibility for the integrity of the work as a

whole, and have given final approval for the

version to be published.

Disclosures. Victoria M. Lim, Eric L.

Maranda, Vivek Patel, Brian J. Simmons and

Joaquin J. Jimenez have nothing to disclose.

Compliance with Ethics Guidelines. This

article is based on previously conducted

studies and does not involve any new studies

of human or animal subjects performed by any

of the authors.

Dermatol Ther (Heidelb) (2016) 6:397–411 409

Open Access. This article is distributed

under the terms of the Creative Commons

Attribution-NonCommercial 4.0 International

License (http://creativecommons.org/licenses/

by-nc/4.0/), which permits any noncommercial

use, distribution, and reproduction in any

medium, provided you give appropriate credit

to the original author(s) and the source, provide

a link to the Creative Commons license, and

indicate if changes were made.

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